Quantification of the effect of in utero events on lifetime resilience in dairy cows.

Currently, the dairy industry is facing many challenges that could affect its sustainability, including climate change and public perception of the industry. As a result, interest is increasing in the concept of identifying resilient animals, those with a long productive lifespan, as well as good reproductive performance and milk yield. There is much evidence that events in utero, that is, the developmental origins of health and disease hypothesis, alter the life-course health of offspring and we hypothesized that these could alter resilience in calves, where resilience is identified using lifetime data. The aim of this study was to quantify lifetime resilience scores (LRS) using an existing scoring system, based on longevity with secondary corrections for age at first calving and calving interval, and to quantify the effects of in utero events on the LRS using 2 datasets. The first was a large dataset of cattle on 83 farms in Great Britain born from 2006 to 2015 and the second was a smaller, more granular dataset of cattle born between 2003 and 2015 in the Langhill research herd at Scotland's Rural College. Events during dam's pregnancy included health events (lameness, mastitis, use of an antibiotic or anti-inflammatory medication), the effect of heat stress as measured by temperature-humidity index, and perturbations in milk yield and quality (somatic cell count, percentage fat, percentage protein and fat:protein ratio). Daughters born to dams that experienced higher temperature-humidity indexes while they were in utero during the first and third trimesters of pregnancy had lower LRS. Daughter LRS were also lower where milk yields or median fat percentages in the first trimester were low, and when milk yields were high in the third trimester. Dam LRS was positively associated with LRS of their offspring; however, as parity of the dam increased, LRS of their calves decreased. Similarly, in the Langhill herd, dams of a higher parity produced calves with lower LRS. Additionally, dams that recorded a high maximum locomotion score in the third trimester of pregnancy were negatively associated with lower calf LRS in the Langhill herd. Our results suggest that events that occur during pregnancy have lifelong consequences for the calf's lifetime performance. However, experience of higher temperature-humidity indexes, higher dam LRS, and mothers in higher parities explained a relatively small proportion of variation in offspring LRS, which suggests that other factors play a substantial role in determining calf LRS. Although "big data" can contain a considerable amount of noise, similar findings between the 2 datasets indicate it is likely these findings are real.

Exploring the relationship between breastfeeding and the incidence of infant illnesses in Ireland: evidence from a nationally representative prospective cohort study.

BACKGROUND: Ireland has one of the lowest BF rates in the world. This study investigates the association between breastfeeding and infant health in Ireland. METHODS: A cross-sectional, secondary analysis of data collected from Growing Up in Ireland (GUI): the National Longitudinal Study of Children was conducted. The average morbidity for 2212. infants exclusively breastfed for at least 90 days (EBF90days) was compared to data for 3987 infants in the non-breastfed (Non-BF) group. Data were weighted using entropy balancing to ensure the comparability of groups. Sensitivity analyses considered alternative definitions of the breastfeeding group. RESULTS: Infants who were EBF90days were significantly less likely to be admitted to hospital (CI: - 0.06 to - 0.03), spent less nights in hospital (CI: - 0.37 to - 0.11), and were less likely to develop respiratory diseases including asthma (CI: - 0.03 to - 0.01), chest infections (CI: - 0.12 to - 0.08), snuffles/common colds (CI: - 0.07 to - 0.02), ear infections (CI: - 0.08 to - 0.04), eczema (CI: - 0.08 to - 0.04), skin problems (CI: - 0.04 to - 0.00), wheezing or asthma (CI: - 0.06 to - 0.03), vomiting (CI: - 0.03 to - 0.00), and colic (CI: - 0.04 to - 0.01). Further outcomes such as current health of the infant at time of interview (CI: - 0.04 to - 0.00), feeding problems (CI: - 0.04 to - 0.02) and sleeping problems (CI: - 0.02 to - 0.00) indicated a protective effect of EBF90days versus Non-BF. However, these infants were also more likely to fail to gain weight (CI: 0.01 to 0.02) and were at a slightly higher risk of developing nappy rash (CI: 0.00 to 0.02). CONCLUSION: Exclusive breastfeeding for 90+ days is associated with protection against childhood morbidity. Given the protective effect of breastfeeding on adverse health effects in infants, policy makers should prioritise policies that support, promote and protect exclusive breastfeeding.

Pharmacology and Rationale for Seralutinib in the Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and myofibroblasts. Platelet-derived growth factor receptors (PDGFR) α and ß, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) are closely related kinases that have been implicated in PAH progression. In addition, emerging data indicate significant crosstalk between PDGF signaling and the bone morphogenetic protein receptor type 2 (BMPR2)/transforming growth factor ß (TGFß) receptor axis. This review will discuss the importance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis, present evidence that the inhibition of all three nodes in this kinase network is a potential therapeutic approach for PAH, and highlight the therapeutic potential of seralutinib, currently in development for PAH, which targets these pathways.

Influence of manure application method on veterinary medicine losses to water.

Veterinary medicines are routinely used within modern animal husbandry, which results in frequent detections within animal manures and slurries. The application of manures to land as a form of organic fertiliser presents a pathway by which these bioactive chemicals can enter the environment. However, to date, there is limited understanding regarding the influence of commonly used manure application methods on veterinary medicine fate in soil systems. To bridge this knowledge gap, a semi-field study was conducted to assess the influence of commonly used application methods such as, broadcast, chisel sweep, and incorporation on veterinary medicine losses to waters. A range of veterinary medicines were selected and applied as a mixture; these were enrofloxacin, florfenicol, lincomycin, meloxicam, oxytetracycline, sulfadiazine, trimethoprim and tylosin. All the assessed veterinary medicines were detected within surface runoff and leachates, and the concentrations generally decreased throughout the irrigation period. The surface runoff concentrations ranged from 0.49 to 183.47 µg/L and 2.26-236.83 µg/L for the bare soil and grass assessments respectively. The leachate concentrations ranged from 0.04 to 309.66 µg/L and 0.33-37.79 µg/L for the bare soil and grass assessments respectively. More advanced application methods (chisel sweep) were found to significantly reduce the mass loads of veterinary medicines transported to surface runoff and leachate by 13-56% and 49-88% over that of broadcast. Incorporating pig slurries reduced the losses further with surface runoff and leachate losses being 13-56% and 49-88% lower than broadcast. Our results show that manure application techniques have a significant effect on veterinary medicine fate in the environment and as such these effects should be considered in the decision-making processes for the management of manures as well as from a risk mitigation perspective for aquatic compartments.

Inhaled seralutinib exhibits potent efficacy in models of pulmonary arterial hypertension.

BACKGROUND: Signalling through platelet-derived growth factor receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor kit (c-KIT) plays a critical role in pulmonary arterial hypertension (PAH). We examined the preclinical efficacy of inhaled seralutinib, a unique small-molecule PDGFR/CSF1R/c-KIT kinase inhibitor in clinical development for PAH, in comparison to a proof-of-concept kinase inhibitor, imatinib. METHODS: Seralutinib and imatinib potency and selectivity were compared. Inhaled seralutinib pharmacokinetics/pharmacodynamics were studied in healthy rats. Efficacy was evaluated in two rat models of PAH: SU5416/Hypoxia (SU5416/H) and monocrotaline pneumonectomy (MCTPN). Effects on inflammatory/cytokine signalling were examined. PDGFR, CSF1R and c-KIT immunohistochemistry in rat and human PAH lung samples and microRNA (miRNA) analysis in the SU5416/H model were performed. RESULTS: Seralutinib potently inhibited PDGFRα/ß, CSF1R and c-KIT. Inhaled seralutinib demonstrated dose-dependent inhibition of lung PDGFR and c-KIT signalling and increased bone morphogenetic protein receptor type 2 (BMPR2). Seralutinib improved cardiopulmonary haemodynamic parameters and reduced small pulmonary artery muscularisation and right ventricle hypertrophy in both models. In the SU5416/H model, seralutinib improved cardiopulmonary haemodynamic parameters, restored lung BMPR2 protein levels and decreased N-terminal pro-brain natriuretic peptide (NT-proBNP), more than imatinib. Quantitative immunohistochemistry in human lung PAH samples demonstrated increased PDGFR, CSF1R and c-KIT. miRNA analysis revealed candidates that could mediate seralutinib effects on BMPR2. CONCLUSIONS: Inhaled seralutinib was an effective treatment of severe PAH in two animal models, with improved cardiopulmonary haemodynamic parameters, a reduction in NT-proBNP, reverse remodelling of pulmonary vascular pathology and improvement in inflammatory biomarkers. Seralutinib showed greater efficacy compared to imatinib in a preclinical study.

Rhinovirus and asthma: Challenges and opportunities.

Human rhinoviruses (RVs) are the primary aetiological agent of the common cold. Generally, the associated infection is mild and self-limiting, but may also be associated with bronchiolitis in infants, pneumonia in the immunocompromised and exacerbation in patients with pulmonary conditions such as asthma or chronic obstructive pulmonary disease. Viral infection accounts for as many as two thirds of asthma exacerbations in children and more than half in adults. Allergy and asthma are major risk factors for more frequent and severe RV-related illnesses. The prevalence of RV-induced wheezing will likely continue to increase given that asthma affects a significant proportion of the population, with allergic asthma accounting for the majority. Several new respiratory viruses and their subgroups have been discovered, with various degrees of relevance. This review will focus on RV infection in the context of the epidemiologic evidence, genetic variability, pathobiology, clinical studies in the context of asthma, differences with other viruses including COVID-19 and current treatment interventions.

The Dark Tetrad, Intimate Partner Violence and the Mediating Role of Moral Disengagement.

PURPOSE: Research suggests that physical, psychological, and/or sexual focussed Intimate Partner Violence (IPV) is related to the dark triad (DT) traits of Machiavellianism, psychopathy, and narcissism. This study extends these findings by considering the addition of everyday sadism into the four-dimension dark tetrad (DTET), testing the possibility that moral disengagement (MD) mediates the relationship between these variables. It was also examined whether the DTET provided incremental validity to the more general personality traits Honesty-Humility, Emotionality, Extraversion, Agreeableness, Conscientiousness, Openness (HEXACO) to predict IPV. METHOD: Males and females (N = 416) from the general population completed five questionnaires in an online survey (HEXACO-60, MMEA, PMDS, CTS2S, SD4). RESULTS: A principal component factor-analysis found that sexual IPV did not load as an individual factor and distinct form of violence on the CTS2S scale so was excluded from this study. Four hierarchical multiple regressions were conducted, using the demographics, HEXACO and either the DTET traits or an overall DTET variable as predictor variables, and either physical or psychological IPV as the dependent variables. Only psychopathy predicted physical and psychological IPV; MD mediated the relationship between psychopathy and psychological IPV. Although the DTET added incremental validity over HEXACO to predict physical IPV, HEXACO low Agreeableness was the strongest predictor of psychological IPV. CONCLUSIONS: Those higher in psychopathy may show different offending trajectories for physical and psychological IPV dependent upon the use of MD processes. Despite the DTET adding incremental validity over the HEXACO dimensions, some HEXACO elements better explain the relationship between personality and psychological IPV than the DTET.

Evaluating Interoceptive Crossover between emotional and physical symptoms.

Symptom perception is complex and influenced by a number of psychological factors, including interoceptive ability and alexithymia. Some individuals may have difficulty distinguishing between internal signals, such as emotions and physical symptoms, however research in this area is sparse. The current study aimed to explore the incidence and nature of this phenomenon, labelled, 'Interoceptive Crossover'. 239 individuals completed an online survey and rated the perceived similarity between a range of emotions (e.g., Sad, Happy, Afraid and Calm) and physical symptoms (e.g., Stomach Pain, Fatigue/Tiredness, Headache and Abnormal Heartbeat) to assess the incidence and nature of Interoceptive Crossover. Individuals demonstrated crossover between emotions and physical symptoms. Some crossovers were more unsurprising and reported by a greater proportion of the sample, such as Afraid and Abnormal Heartbeat (74.5%); Sad and Fatigue (29.4%) and Afraid and Shortness of Breath (58.5%). Other crossovers were less prevalent in the sample and more unexpected such as Satisfied with Headache (1.2%); Bored with Back Pain (5.95%) and Happy and Back Pain (0.4%). Overall, individuals demonstrate Interoceptive Crossover of emotions and physical symptoms and some crossovers are more prevalent whilst others are rare and unexpected. This phenomenon needs further study with respect to relevant constructs including alexithymia and interoception.

Emotion Regulation Mediates Posttraumatic Growth and Cluster B Personality Traits After Childhood Trauma.

OBJECTIVES: Cluster B personality disorder traits and positive psychological change, known as posttraumatic growth (PTG), are both possible outcomes following childhood trauma. However, existing research has not yet explored whether emotion regulation difficulties can simultaneously explain these negative and positive changes. METHOD: A sample of childhood trauma survivors (N = 223) provided responses to an online survey, with findings assessed using structural equation modeling techniques. RESULTS: Emotion regulation difficulties were found to mediate between childhood trauma severity and cluster B traits (ab cs = -.05), and between childhood trauma severity and PTG (abcs = .13), with small to medium indirect effects. The final model accounted for more variance in cluster B traits (56%) than PTG (10%). CONCLUSIONS: Emotion regulation is therefore a key mediator of positive and negative psychological changes and should be the focus of intervention efforts among childhood trauma survivors.

Pharmaceutical and Personal Care Products: From Wastewater Treatment into Agro-Food Systems.

Irrigation with treated wastewater (TWW) and application of biosolids introduce numerous pharmaceutical and personal care products (PPCPs) into agro-food systems. While the use of TWW and biosolids has many societal benefits, introduction of PPCPs in production agriculture poses potential food safety and human health risks. A comprehensive risk assessment and management scheme of PPCPs in agro-food systems is limited by multiple factors, not least the sheer number of investigated compounds and their diverse structures. Here we follow the fate of PPCPs in the water-soil-produce continuum by considering processes and variables that influence PPCP transfer and accumulation. By analyzing the steps in the soil-plant-human diet nexus, we propose a tiered framework as a path forward to prioritize PPCPs that could have a high potential for plant accumulation and thus pose greatest risk. This article examines research progress to date and current research challenges, highlighting the potential value of leveraging existing knowledge from decades of research on other chemicals such as pesticides. A process-driven scheme is outlined to derive a short list that may be used to refocus our future research efforts on PPCPs and other analogous emerging contaminants in agro-food systems.

Inhibiting Oxidative Phosphorylation In Vivo Restrains Th17 Effector Responses and Ameliorates Murine Colitis.

Integration of signaling and metabolic pathways enables and sustains lymphocyte function. Whereas metabolic changes occurring during T cell activation are well characterized, the metabolic demands of differentiated T lymphocytes are largely unexplored. In this study, we defined the bioenergetics of Th17 effector cells generated in vivo. These cells depend on oxidative phosphorylation (OXPHOS) for energy and cytokine production. Mechanistically, the essential role of OXPHOS in Th17 cells results from their limited capacity to increase glycolysis in response to metabolic stresses. This metabolic program is observed in mouse and human Th17 cells, including those isolated from Crohn disease patients, and it is linked to disease, as inhibiting OXPHOS reduces the severity of murine colitis and psoriasis. These studies highlight the importance of analyzing metabolism in effector lymphocytes within in vivo inflammatory contexts and suggest a therapeutic role for manipulating OXPHOS in Th17-driven diseases.

Estimating the health-care costs of wound care in Ireland.

OBJECTIVE: To estimate the cost of wound care to the Irish health-care system. METHODS: A bottom-up, prevalence-based analysis was undertaken using a decision analytic model to estimate costs. Health-care resource activity was identified from a recently published study from the UK and was valued using unit cost data for Ireland. RESULTS: The base case analysis estimated the total annual healthcare cost of wound care to be €629,064,198 (95% Confidence interval (CI): €452,673,358 to €844,087,124), accounting for 5% (95% CI: 3% to 6%) of total public health expenditure in Ireland in 2013. The average cost per patient was €3,941 (95% CI: €2,836 to €5,287). However, this study is subject to many limitations and plausible changes in the model's inputs showed that the total annual health-care cost of wound care could range from €281,438,970 to €844,316,912. CONCLUSION: Caring for wounds places a substantial burden on the Irish health-care system. In light of growing pressures to finance an already resource-constrained health-care system, these results provide useful information for those charged with future wound care service design and provision in Ireland and elsewhere.

Barriers to Oral Food Intake for Children Admitted to Hospital.

Children are at risk for malnutrition in hospital, and a contributing factor may be poor oral intake. Barriers to intake have been studied in adults, but there is a lack of research in children. The purpose of this study was to identify the potential barriers to oral intake for children in hospital. Patients and families (n = 58) admitted to surgery and medicine units at the Stollery Children's Hospital completed a survey on barriers to oral food intake. Barriers were classified into 6 domains and major barriers were those identified by at least 30% of the population. On average each patient was affected by 22% of the barriers. Within each domain, the proportion of patients identifying at least 1 barrier was as follows: organization (74%), hunger (67%), quality (60%), effects of illness (53%), choice (38%), and physical limitations (29%). Having food brought in from home due to hunger, not wanting what was ordered once it arrives, food quality, decreased appetite, sickness, fatigue, and pain were identified as major barriers. Children have unique barriers to oral food intake in hospital which have not been previously identified. Food service models should consider these barriers to better meet the needs of this population.

Application of prioritization approaches to optimize environmental monitoring and testing of pharmaceuticals.

Pharmaceuticals are ubiquitous in the natural environment with concentrations expected to rise as human population increases. Environmental risk assessments are available for a small portion of pharmaceuticals in use, raising concerns over the potential risks posed by other drugs that have little or no data. With >1900 active pharmaceutical ingredients in use, it would be a major task to test all of the compounds with little or no data. Desk-based prioritization studies provide a potential solution by identifying those substances that are likely to pose the greatest risk to the environment and which, therefore, need to be considered a priority for further study. The aim of this review was to (1) provide an overview of different prioritization exercises performed for pharmaceuticals in the environment and the results obtained; and (2) propose a new holistic risk-based prioritization framework for drugs in the environment. The suggested models to underpin this framework are discussed in terms of validity and applicability. The availability of data required to run the models was assessed and data gaps identified. The implementation of this framework may harmonize pharmaceutical prioritization efforts and ensure that, in the future, experimental resources are focused on molecules, endpoints, and environmental compartments that are biologically relevant.

The Woodhull Study Revisited: Nurses' Representation in Health News Media 20 Years Later.

PURPOSE: To determine if nurses are represented in health news stories more frequently today than 20 years ago when Sigma Theta Tau International Nursing Honorary Society published The Woodhull Study on Nursing and the Media, which found that nurses were cited as sources in only 4% of the stories. DESIGN: Content analysis of health news stories for the month of September 2017 in the same publications used in the original Woodhull study. METHODS: Searches with Nexis and Webhose identified 2,243 articles related to health care published by the news outlets in September 2017. A random sample of 537 of these articles was obtained: 258 from seven newspapers, 127 from three weekly newsmagazines, and 152 from three health industry publications. After removing irrelevant articles or those with only passing references to health, 365 articles were reviewed and coded, using the original study's coding schema. FINDINGS: Nurses were identified as the source of only 2% of quotes in the articles and were never sourced in stories on health policy. When quoted, nurses mainly commented on the profession itself. Nurses or the nursing profession were mentioned in 13% of the articles. Nurses were identified in 4% of photographs or other images that accompanied the articles. CONCLUSIONS: Nurses remain invisible in health news media, despite their increasing levels of education, unique roles, and expertise. CLINICAL RELEVANCE: Nurses' clinical expertise is accompanied by unique perspectives on health, illness, and health care; but the public is not benefiting from the wisdom and insight that nurses can provide in health news stories.

Detection, Occurrence and Fate of Emerging Contaminants in Agricultural Environments.

A total of 75 papers published in 2017 were reviewed ranging from detailed descriptions of analytical methods, to fate and occurrence studies, to ecological effects and sampling techniques for a wide variety of emerging contaminants likely to occur in agricultural environments. New methods and studies on veterinary pharmaceuticals, steroids, antibiotic resistance genes, and engineered nanoparticles agricultural environments continue to expand our knowledge base on the occurrence and potential impacts of these compounds. This review is divided into the following sections: Introduction, Analytical Methods, Fate and Occurrence, Pharmaceutical Metabolites, Anthelmintics, Antibiotic Resistence Genes, and Engineered Nanomaterials.

Sterol metabolism controls T(H)17 differentiation by generating endogenous RORγ agonists.

Retinoic acid receptor-related orphan receptor γ (RORγt) controls the differentiation of naive CD4(+) T cells into the TH17 lineage, which are critical cells in the pathogenesis of autoimmune diseases. Here we report that during TH17 differentiation, cholesterol biosynthesis and uptake programs are induced, whereas their metabolism and efflux programs are suppressed. These changes result in the accumulation of the cholesterol precursor, desmosterol, which functions as a potent endogenous RORγ agonist. Generation of cholesterol precursors is essential for TH17 differentiation as blocking cholesterol synthesis with chemical inhibitors at steps before the formation of active precursors reduces differentiation. Upon activation, metabolic changes also lead to production of specific sterol-sulfate conjugates that favor activation of RORγ over the TH17-inhibiting sterol receptor LXR. Thus, TH17 differentiation is orchestrated by coordinated sterol synthesis, mobilization and metabolism to selectively activate RORγ.

Novel Approach for Characterizing pH-Dependent Uptake of Ionizable Chemicals in Aquatic Organisms.

Here, we present and evaluate a combined experimental and modeling approach for characterizing the uptake of ionizable chemicals from water and sediments into aquatic organisms under different pH conditions. We illustrate and evaluate the approach for two pharmaceuticals (diclofenac and fluoxetine) and one personal care product ingredient (triclosan) for the oligochaete Lumbriculus variegatus. Initially, experimental data on the uptake of the three chemicals at two pH values were fitted using a toxicokinetic model to derive uptake and depuration constants for the neutral and ionized species of each molecule. The derived constants were then used to predict uptake from water and sediment for other pH conditions. Evaluation of predictions against corresponding experimental data showed good predictions of uptake for all test chemicals from water for different pH conditions and reasonable predictions of uptake of fluoxetine and diclofenac from a sediment. Predictions demonstrated that the level of uptake of the study chemicals, across pH ranges in European streams, could differ by up to a factor of 3035. Overall, the approach could be extremely useful for assessing internal exposure of aquatic organisms across landscapes with differing pH. This could help support better characterization of the risks of ionizable chemicals in the aquatic environment.